Enkephalin, a natural opiate receptor agonist in the brain, has been identified [see Hughes et al., Nature, 258,577 (1975)] as a mixture of two pentapeptides: H-Tyr-Gly-Gly-Phe-Met-OH (methionine-enkephalin) and H-Tyr-Gly-Gly-Phe-Leu-OH (leucine-enkephalin). Both peptides mimic the ability of morphine to block electrically evoked contractions of mouse vas deferens and guinea pig ileum, and both inhibit the stereospecific receptor binding of the opiate antagonist 3H-naloxone in brain homogenates. It has been reported that methionine-enkephalin and leucine-enkephalin, when administered by injection in the brain ventricle in rats, induce a profound analgesia that is fully reversible by naloxone. [See Beluzzi et al., Nature, 260, 625 (1976)]. The enkephalins are inactive peripherally, however, and it is believed that the enkephalins are rapidly destroyed by blood enzymes and/or are poorly transported across the blood-brain barrier.
Various structural variations of methionine-enkephalin and leucine-enkephalin are described in the literature. For example, the pentapeptide H-Tyr-Gly-Gly-Phe-Thr-OH, wherein the fifth amino acid residue (methionine or leucine) is replaced by threonine, is described by Chang et al., Life Sciences, 18, 1473 (1976). Similarly, a long acting synthetic pentapeptide, Tyr-D-Ala-Gly-Phe-Met amide is described in Pert et al., Science, 194, 330 (1976); like the natural enkephalins, it is inactive peripherally, for example upon intravenous administration. Baxter et al., British Pharmaceutical Society Proceedings, Jan. 5-7, 1977, page 455P and 523P, report the i.c.v. activity of Tyr-D-Ala-Gly-Phe-D-Leu. Bajusz et al., FEBS Letters, 76, 91 (1977), by replacing Gly.sup.2 with D-Met and Met.sup.5 by Pro-NH.sub.2, obtained a very potent antinociceptive pentapeptide Tyr-D-Met-Gly-Phe-Pro-NH.sub.2 which was 5.5 times more potent than morphine by intravenous administration. Romer et al., Nature, 268, 547 (1977) have shown that: ##STR3## is a potent analgesic when administered peripherally and provides some analgesia when administered orally at high doses (200-300 ng/kg.). Morgan et al., Peptides, Proc. Fifth Amer. Pept. Symp., Ed. Goodman and Meienhofer, p. 111 (1977) reported in vitro and in vivo biological activities of several enkephalin analogs such as N(CH.sub.3)Tyr-Gly-Gly-Phe-Met-NH-propyl. Ling et al., ibid, p. 96 (1977) reported in vitro biological activities of several enkephalin analogs containing D-amino acids in 5-position. Dutta et al., Life Sciences, 21, 559 (1977) and Acta. Pharm. Sciences, 14, 14 (1977) described enkephalin analogues containing in 2-position D-Ser, D-Met, D-Ala, D-Thr, D-Lys(Boc), D-Phe, D-Leu, D-Asp and D-Ser (t-Bu) in conjunction with various L-amino acids and other amine in 5-position. belluzzi et al., Life Sciences, 23, 99 (1978) have described enkephalin analogues containing D-Ala.sup.2 and D-Leu.sup.5 or D-Met.